Cigarette smoking is the leading cause of preventable death in the USA. In 2009, Congress passed the Tobacco Control Act and authorized the FDA to regulate cigarette ingredients to reduce their harm to the public. Therefore, knowledge of factors contributing to the addictive properties of cigarette smoking is urgently needed. The aim of the proposed project is to test the hypothesis that nitric oxide (NO) in cigarette smoke enhances the addictive properties of cigarette smoking by facilitating nicotine inhalation and absorption. NO is an endogenous signaling gas and a powerful dilator of airways and pulmonary vessels, and important for normal pulmonary function. Chronic smoking reduces NO production, induces an inflammation process in the pulmonary system, increases resistance of airways and pulmonary vessels, and may finally result in chronic obstructive pulmonary disease (COPD) and pulmonary hypertension. Inhaled cigarette smoke contains a high level of NO which may increase inhalation volume and pulmonary perfusion and air exchange by dilating airways and pulmonary vessels and reducing their resistance, thus facilitating nicotine inhalation and absorption, especially in chronic smokers with impaired pulmonary function. Relevant to this potential role of NO, cigarette manufacturers increased the NO in smoke by increasing nitrate, a main precursor of NO, in cigarettes, even though they reduced nicotine and tar during the same period from the 1950s-1990s. The increased NO may contribute to the so-called smoking compensation; i.e., tobacco-dependent smokers inhale deeper when smoking nicotine-reduced cigarettes relative to regular cigarettes. To test whether NO facilitates nicotine absorption, we will ask tobacco-dependent smokers to participate in two smoking sessions on two different days after overnight abstinence. Smokers will smoke a regular cigarette through a filter during each study session. The filter will remove NO from mainstream smoke during one session (i.e., real filter session (RFS)) but will not remove NO during the other session (i.e., dummy filter session (DFS)). Blood samples for assessing plasma nicotine levels will be acquired both before and after smoking during each session. Compared with the RFS, a significantly greater increase in plasma nicotine levels after smoking relative to before smoking in the DFS will support our hypothesis that NO facilitates nicotine absorption during cigarette smoking. We will acquire measures on craving, negative affect, and smoking effects during each session for comparing subjective effects of smoking during the two sessions. Positive findings from the proposed study will provide a foundation for subsequent studies assessing more fully a role for NO in tobacco-use disorder. The goal of these studies is to generate data for the FDA to decide whether and how to regulate NO and/or its precursors (e.g., nitrate) in cigarettes to promote public health by reducing the addictive properties of cigarette smoking.